Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide

Abstract 

Hydrogen sulfide (H₂S) is an essential physiological product in brain. We investigated the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CGL), the two H₂S synthesizing enzymes, in human cell lines and in human brain. Only astrocytes were strongly immunostained for CBS. Cultured astrocytes synthesized H₂S at the rate of 15.06μmol/g protein/h, which was 7.57 fold higher than microglial cells, 10.27 fold higher than SH-SY5Y cells and 11.32 fold higher than NT-2 cells. The H₂S synthesis in all these cell types was inhibited by the CBS inhibitor hydroxylamine, but not by the CGL inhibitor propargylglycine (PAG). Synthesis of H₂S by HUVEC cells was inhibited by PAG but not by hydroxylamine indicating that these vascular cells utilize CGL but not CBS. Inflammatory activation of microglia and astrocytes caused induction of NFκB, release of the inflammatory mediators TNFα, IL-6 and nitrite ions, down-regulation of CBS, and down-regulation of H₂S synthesis. There was no effect of such treatment on HUVEC cells. The effects were partially reversed by pretreatment of cells with the H₂S releasing agent NaSH. These data indicate that H₂S is an endogenous antiinflammatory and neuroprotective agent under the synthetic control of CBS. H₂S releasing drugs may have therapeutic potential in neurodegenerative disorders of aging such as Alzheimer disease and Parkinson disease.

Keywords: Cystathionine-β-synthase, Microglia, Alzheimer disease, Parkinson disease, Aging, Neuroinflammation, NaSH